Director's Report to the National Advisory Council on Drug Abuse
May, 1998

Research Findings

Behavioral Research

Anti-Craving Medications and Incentive Motivation

Environmental cues associated with drugs of abuse may elicit craving and contribute to relapse. A 'reinstatement' model of self-administration with cocaine has been proposed to mimic the incentive motivational properties of these cues. In phase I of the experiment rats were trained to press a lever to receive a cocaine infusion in the presence of certain environmental cues. In phase II, in the absence of the previously paired environmental cues, these rats continued to press the lever but were not given cocaine and eventually bar pressing stopped. In phase III, however, when the original environmental cues were re-introduced, control rats began to bar press again wheras experimental rats chronically administered DMI, a noradrenergic reuptake blocker, did not return to bar pressing. This suggests that these cues activate motivational processes which drive drug-seeking behavior. Dr. Janet Neisewander at Arizona State University recently reported that chronic treatment with a noradrenergic reuptake blocker, desmethylimipramine (10 mg/kg DMI/day), attenuated responses made on the drug lever following cue presentation in extinction. As DMI has been demonstrated to possess 'anti-craving' properties in some patient populations, this observation suggests that a possible mechanism for this anti-craving effect may be the blockade of incentive motivational properties associated with drug-related stimuli. Fuchs, R.A., Tran-Nguyen, T.L., Specio, J.E., Groff, R.S., Neisewander, J.L. Psychopharmacology. 135, pp. 151-160, 1998.

Cocaine Effects on Cocaine Versus Food-Maintained Responding

This project by Dr. J.R. Glowa is examining the effects of continuously infusing cocaine on cocaine- versus food-maintained operant responding in rhesus monkeys. When animals worked to self-administer low doses of cocaine (10 &g/kg/injection), additional non-contingent continuous cocaine infusion decreased such responding in a dose-related manner but without affecting food-maintained responding. In contrast, when animals self-administered at higher doses of cocaine (56 &g/kg/injection), additional cocaine infusion decreased both cocaine- and food- maintained responding. These data show that long-acting agonist approaches to pharmaco-therapy of cocaine are viable, but are dependent on dose and the event that maintains responding. Glowa, J.R., Fantegrossi, W.E. Drug and Alcohol Dependence.45, pp.71-79, 1997.

Establishing Preference for Oral Cocaine

In prior research, Dr. John L. Falk has shown in rats that preference for oral cocaine, as well as preference for non-reinforcing lidocaine, can be established by pairing it with a highly palatable vehicle such as dilute ethanol or a glucose/saccharin solution which is then slowly faded out. Dr. Falk has now reported that preference for cocaine can also be established by exposing the rats to a history of choosing cocaine in preference to lidocaine. This work along with the prior work suggest that two kinds of historical associations may be involved in the establishment of drugs as reinforcers: Drug preference can be acquired, on the one hand, by the avoidance of an aversive alternative; and, it can also result from a past association with a positively reinforcing social context. This work makes it clear that pharmacological consequences often may not be the major factor initiating and sustaining chronic drug-taking. The person's history of an association of drug-taking with the satisfaction of other motives allows drug-seeking and drug-taking behavior to be maintained at a high level long after the original motives are no longer operative. Falk, J.L., Lau, C.E. Establishing Preference for Oral Cocaine Without an Associative History with a Reinforcer. Drug and Alcohol Dependence. 46, pp. 159-166, 1997.

The possibility of a relation between morphine's immunosuppressive effects and its analgesic effects was examined by comparing the time courses of these two measures. Following a subcutaneous injection of morphine (15 mg/kg), immune system measures (i.e., NK activity, proliferation of T- and B-cells and cytokine production) and antinociception (using the tail-withdrawal assay) were assessed across a 24-hr period. Maximal suppression occurred after 1 hr with recovery complete within 24 hours, while morphine-induced antinociception occurred in 30 minutes to 2 hours, with recovery complete within 6 hours. These results suggest that different mechanisms may be modulating morphine's immunosuppressive effects and its analgesic effects. Nelson, C.J., Dykstra, L.A., Lysle, D.T. Anesthesia and Analgesia. 85, pp. 620-626, 1997.

Effects of Rearing on Morphine-Induced Behavior and Neurology

Rats were raised from weaning (21 days old) to young adulthood (50-60 days old) in either an enriched or impoverished stimulus environment. In the enriched condition (EC), rats were group-housed with various novel objects that were re-arranged daily. In the impoverished condition (IC), rats were housed individually without any objects. As adults, a four-trial conditioned place preference (CPP) test was used to assess locomotor activity and reward produced by morphine (0, 0.1, 1 or 10 mg/kg). On morphine conditioning day 1, both EC and IC rats displayed an inverted U-shaped dose-effect curve for locomotor activity and the locomotor stimulant effect of acute morphine was greater in IC than EC rats. Across morphine conditioning days 1-4, both EC and IC rats displayed locomotor sensitization; the locomotor sensitization following repeated morphine injections was greater in IC than EC rats. In contrast to the enhanced locomotor stimulant effect of morphine observed in IC rats, morphine-induced CPP was attenuated in IC rats relative to EC rats, indicating that the locomotor and rewarding effects of opioids depend upon different neural substrates. Measurement of mu opioid receptor density and rates of morphine-stimulated dopamine synthesis in the mesolimbic and nigrostriatal systems of EC and IC rats revealed no reliable differences between groups. Therefore, the ability of mu opioid receptors to modulate mesolimbic dopamine neurotransmission does not account for the differential behavioral effects of morphine in EC and IC rats. Bardo, M.T., Robinet P.M., & Hammer, R.F., Jr. Effect of Differential Rearing Environments on Morphine-Induced Behaviors, Opioid Receptors and Dopamine Synthesis. Neuropharmacology. 36(2), pp. 251-259, 1997.